T-butoxycarbonylaminoethylamine for the Synthesis of PNA Monomer Units, Amino Acid Derivatives, Intermediates Thereof, and Processes for Productions of Them

ABSTRACT

A process for amino acid derivatives shown by the below general formula (I): 
     
       
         
         
             
             
         
       
     
     (wherein R 1  means a hydrogen atom or a straight chain or branched chain alkyl group with 1-5 carbon atoms.) having an object to provide a process of the amino acid derivatives of the formula (I) and their synthetic intermediate, t-butoxycarbonylamino-ethylamine, whereby it requires no tedious procedure and is also good in yield, and its application to a mass production is easy, and to provide novel amino acid derivatives of the formula (IV), their synthetic intermediates, and a process thereof, characterized in that it comprises a step to obtain the amino acid derivatives shown by the general formula (I) by hydrolysis of compounds shown by the below formula (II): 
     
       
         
         
             
             
         
       
     
     (wherein R 1  has the same meaning as described above, and R 2  means a straight chain or branched chain alkyl group with 1-4 carbon atoms.) as well as amino acid derivatives shown by the general formula (IV): 
     
       
         
         
             
             
         
       
     
     (wherein R 1  means a hydrogen atom or a straight chain or branched chain alkyl group with 1-5 carbon atoms, and n means any one of integers 1-11.), and a process for the amino acid derivative, characterized in that it comprises a reduction step of benzyloxycarbonyl-ω-amino acid derivatives.

t-Butoxycarbonylaminoethylamine, amino acid derivatives and theirintermediates for synthesis of PNA monomer units as well as processthereof.

TECHNICAL FIELD OF THE INVENTION

The invention relates to a process for amino acid derivatives andt-butoxycarbonylaminoethylamine which is their intermediate, and moreparticularly relates to a process for amino acid derivatives andt-butoxycarbonylaminoethylamine which is their intermediate, expedientlyused as a base or a base substance for introducing a functional moleculein case of synthesizing a monomer unit for syntheses of Boc-type PNA, anamino acid derivative introducing a Boc-type functional molecule and thelike.

BACKGROUND ART

Amino acid derivatives shown by the below formula (I)

(wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl groups with 1-5 carbon atoms. Hereinafter it is same.) have a widevariety of use as a base or a base substance for introducing afunctional molecule in case of synthesizing a monomer unit for synthesisof Boc-type PNA, an amino acid derivative introducing a Boc-typefunctional molecule and the like.

In particular, as shown in FIG. 1, PNA (Peptide Nucleic Acid) has thestructure in which the sugar phosphoric acid skeleton in a naturalnucleic acid such as DNA is converted into the N-(2-aminoethyl)glycineskeleton, is high in a double strand formation performance and a basesequence recognition performance compared with a natural nucleic acid,further is intact for an in vivo nuclease and protease, and thereforeits application to a gene therapy as an antisence molecule is examined,attracting attention in recent years. The above characteristics of PNAis due to the fact that the sugar phosphoric acid skeleton in a naturalnucleic acid has negative charge in neutral conditions whereby anelectrostatic repulsion between complementary chains is produced, and incontrast in PNA having N-(2-aminoethyl)glycine skeleton without chargeno electrostatic repulsion is produced between complementary chains.

Synthesis of PNA is carried out by sequentially combining an amino acid(especially glycine) derivative (monomer unit) which is introduced byany one of four kinds of bases (A, T (U), C and G) constituting DNA orRNA according to an aimed base sequence using a conventional solidpeptide synthesis method. As for monomer units for the synthesis of PNA,there are two types, Fmoc type and Boc type, as shown in FIG. 2 (Brepresents base), though synthetic methods of monomer units areestablished and use of a Fmoc type which, enables to utilize a generalDNA automatic synthesis machine to synthesize a PNA oligomer currentlyhas become a major trend. However, because in case of synthesizing PNAby use of a Boc type monomer unit there is an advantage that afunctional molecule unstable in basic conditions can be introduced inPNA, establishment of a PNA synthesis method using a Boc type monomerunit becomes an urgent matter.

As one of obstacles to hinder establishment of a PNA synthesis methodusing a Boc type monomer unit, it can be cited that a simple and cheapsynthesis method for a monomer unit before introduction of a base, thatis, a Boc type amino acid derivative shown in the formula (I), is not tobe established. Also, because an amino acid derivative of the formula(I) has use as a base substance for introducing other functionalmolecule in stead of the base, synthesis of an amino acid derivativeintroducing a functional molecule becomes easy if its simple and cheapsynthesis method is established.

The synthetic method for an amino acid derivative of the formula (I)usually makes ethylenediamine a starting material and contains a step tointroduce t-butoxycarbonyl group (Boc) to one nitrogen atom and a stepto introduce —CHR¹—COOH to the other nitrogen.

As a method to obtain t-butoxycarbonylaminoethylamine by introduction ofBoc to one nitrogen atom of ethylenediamine, for example, (1) methodsare reported in which t-butoxycarboxylic acid anhydride is directlyreacted to ethylenediamine in a reaction solvent such as chloroform,methanol or dioxane (J. Med. Chem., 38(22), 4433-8; 1995, Bull. KoreanChem. Soc., 15(12), 1025-7; 1994, Eur. J. Med. Chem., 26(9), 915-20;1991, Synth. Commun., 20(16), 2559-64; 1990, Aust. J. Chem., 39(3),447-55; 1986),

and (2) a method in which t-butoxycarboxylic acid anhydride is convertedto an active ester followed by reaction with ethylenediamine (JP, A11-012234,).

Also, as a method to obtain an amino acid derivative of the formula (I)by introduction of —CHR¹—COOH to t-butoxycarbonylaminoethylamine, amethod is reported in which benzyl group is introduced to theunprotected nitrogen atom of t-butoxycarbonylaminoethylamine, (3)followed by reaction with benzyl bromoacetate and then by the catalyticreduction (J. Org. Chem., 62(2), 411-416; 1997).

Further, as a method to obtain an amino acid derivative of the formula(I) by introduction of Boc to the other nitrogen atom of theethylenediamine derivative in which —CHR¹—COOH is introduced to onenitrogen atom, (4) a method is reported in which t-butoxycarboxylic acidanhydride is reacted to N-(2-aminoethyl)glycine (Heimer, E. P.;Gallo-Torres, H. E.; Felix, A. M.; Ahmad, M.; Lambros, T. J.; Scheidl,F.; Meienhofer, J. Int. J. Pept. Protein Res. 23(2), 203-211, 1984).

However, as a method to prepare t-butoxycarbonylamino-ethylamine, in themethod 1 the aimed substance can be obtained in relatively good yield,though di(t-butoxycarbonylamino)ethylene and t-butoxycarboxylic acid areproduced as byproducts, existing in a reaction solvent such aschloroform, methanol or dioxane. Owing to this, a partition extractionprocedure or partition chromatography are necessary, making it difficultto prepare t-butoxycarbonylaminoethylamine efficiently in a large amountand cheaply.

Also, although the method 2 has an advantage thatdi(t-butoxycarbonylamino)ethylene is not produced as a byproduct, thetotal yield is as low as about 60% due to a multistep reaction, andbecause used reagents must be removed by partition chromatography, it isdifficult to prepare t-butoxycarbonylaminoethylamine efficiently in alarge amount and cheaply just like the method 1.

Therefore, both methods 1 and 2 are inappropriate as a method toindustrially prepare t-butoxycarbonylaminoethylamine.

Also, as a method to obtain an amino acid derivative of the formula (I)from t-butoxycarbonylaminoethylamine, the method 3 is a multistepreaction, and a partition extraction procedure is necessary, beinginappropriate for an industrial preparation.

Further, as a method to obtain an amino acid derivative of the formula(I), the method 4 has an advantage that partition chromatography isunnecessary, though the yield is around 60%, being inappropriate for anindustrial preparation. That is, an efficient method to obtain aphoto-functional PNA molecule has not been established due to a lowefficiency in the synthesis of an amino acid derivative of the formula(I). Therefore, needed are a method to obtain an amino acid derivativeof the formula (I) and the development of the amino acid derivative tomake a more efficient synthesis of the photo-functional PNA moleculepossible in case of using an amino acid derivative of the formula (I).

DISCLOSURE OF THE INVENTION

The invention is accomplished in view of these circumstances, and theobject is to provide novel amino acid derivatives shown by the formula(IV), as is afterwards described, their synthetic intermediates and aprocess thereof.

In relation to above described object, inventors developed a process ofamino acid derivatives shown by the formula (I) below:

(wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms.), by hydrolysis of compounds shown bythe formula (II) below:

(wherein R¹ has the same meaning as described above, and R² means astraight chain or branched chain alkyl group with 1-4 carbon atoms.) asa process of amino acid derivatives shown by above formula (I),

and developed a process of compound shown by the formula (II), which isobtained by reaction of t-butoxycarbonylaminoethylamine and a compoundshown by the formula (III) below

(wherein R¹ and R² have the same meanings as described above.)

Grounding on a background of developing a process of a compound shown byabove formula (I), and a process of compound shown by above formula(III), the invention relates to amino acid derivatives shown by thegeneral formula (IV):

(wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms, and n means any one of integers1-11.).

Further, the invention relates to intermediates of the amino acidderivatives shown by the above general formula (IV) which are shown bythe general formula (V):

(wherein R¹ and n have the same meanings as described above.)

Also, the invention relates to intermediates of the amino acidderivatives shown by the above general formula (IV) which are shown bythe general formula (VI):

(wherein R¹ and n have the same meanings as described above, and R²means a straight chain or branched chain alkyl groups with 1-4 carbonatoms.).

Further, the invention relates to a process for the amino acidderivatives shown by the above general formula (IV), comprising a stepto obtain the compounds of the general formula (V).

Also, the invention relates to the above process, characterized in thatthe reduction of the compounds shown by the general formula (V) iscarried out in a methanol solution containing palladium carbon as acatalyst.

Further, the invention relates to the above process, characterized inthat it contains a step to obtain the compounds shown by the generalformula (V) by hydrolysis of the compounds shown by the general formula(VI).

Also, the invention relates to the above process, characterized in thatthe hydrolysis of the compounds shown by the general formula (VI) iscarried out by an aqueous alkaline metal hydroxide solution.

Furthermore, the invention relates to the above process, characterizedin that it contains a further step in which the alkaline metal ion isremoved by cation-exchange chromatography using pyridinium ion as acounter ion.

Also, the invention relates to the above process, characterized in thatthe alkaline metal is lithium, sodium or potassium.

And the invention relates to the above process, characterized in thatthe compounds shown by the general formula (VI) are obtained by reactionof benzyloxycarbonyl-ω-amino acids shown by the general formula (VII)below:

(wherein n has the same meaning as described above.).and the compounds shown by the general formula (II).

And the invention relates to the above process, characterized in that inthe compounds shown by any one of the general formulas (II) and(IV)-(VII) R¹ is a hydrogen atom, R² is an ethyl group, and n is 1.

Also, the invention relates to a process for the compounds shown by thegeneral formula (V), characterized in that it contains a step to obtainthe compounds shown by the general formula (V) by hydrolysis of thecompounds shown by the general formula (VI).

Further, the invention relates to a process for the compounds shown bythe general formula (VI), characterized in that it contains a step toobtain the compounds shown by the general formula (VI) by reaction of abenzyloxycarbonyl-ω-amino acid shown by the general formula (VII) and acompound of the general formula (II).

Furthermore, the invention relates to the use of the compounds shown bythe above general formula (IV) in the preparation of a Boc type PNAmonomer unit.

Also, the invention relates to the use of the compounds shown by theabove general formula (V) in the preparation of a Boc type PNA monomerunit.

And the invention relates to the use of the compounds shown by the abovegeneral formula (VI) in the preparation of a Boc type PNA monomer unit.

Since in the compounds shown by the general formula (IV) a linker bindsbeforehand, they are rich in versatility, and an aimed PNA monomer unitcan be obtained in one step by reaction of an active ester with saidcompounds. Therefore, since according to the compounds shown by theformula (IV) a photo-functional molecule can be converted into a PNAmonomer unit by less synthetic steps compared with current methods, saidcompounds are particularly effective in case of targeting a relativelyexpensive photo-functional molecule.

In the meantime, making a photo-functional molecule which is a sulfonicacid chloride type and has a big steric hindrance and the like into aPNA monomer can be carried out using the compounds shown by the generalformula (I). Therefore, various kinds of functional PNA monomers can besynthesized according to the invention.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1-1 and FIG. 1-2 are illustrations to show the structures comparinga natural nucleic acid with a peptide nucleic acid.

FIG. 2 is illustrations to show comparing with a Fmoc type monomer unitand a Boc type monomer unit.

In each figure; 1 and 2 show a sugar phosphoric acid skeleton and aN-(2-aminoethyl)glycine skeleton, respectively.

EMBODIMENT OF THE INVENTION

In the following, an embodiment of the invention is explained in moredetail.

The amino acid derivatives shown by the formula (IV) of the inventionare prepared by the steps shown below using the compounds shown in theprevious general formula (II).

The first step is, as described below, the step to prepare thebenzyloxycarbonyl-ω-amino acid-^(BOC)PNA-OR² by the reaction of thecompound ^(BOC)PNA-OR² shown by the general formula (II) with thebenzyloxycarbonyl-ω-amino acid shown by the general formula (VII) usingdimethylformamide (DMF) or the like as the solvent and triethylamine.

The solvent DMF, the compounds (II), (VII) and the EDCI derived productcan be separable from the aimed substance (VI) by a partition procedure.Since theoretically only the aimed substance (VI) remains in an organiclayer, purification by column is unnecessary, though just to be surepurification was done. The aimed substance was obtained quantitativelyby this method.

The subsequent step is the step to prepare the benzyloxycarbonyl-ω-aminoacid-^(BOC)PNA-OH shown by the general formula (V) by hydrolysis of thebenzyloxycarbonyl-ω-amino acid-^(BOC)PNA-OR shown by the general formula(VI).

The hydrolysis is preferably carried out in an aqueous alkaline metalhydroxide solution. As an alkaline metal, lithium, sodium or potassiumare preferable, and in particular sodium is preferable. Further, thecondition of hydrolysis is under ice-cooling or at room temperature.

Subsequently, the step to obtain the compound, the final step, shown bythe general formula (IV) is carried out.

This step is preferably carried out in a methanol solution containingpalladium carbon as a catalyst.

As a method to synthesize the compound (IV) from the compound (VI), themethod via (V) is the only method. For example, as in the followingfigures, in case (VI) is first subjected to a catalytic reduction, thecyclic compound is formed via the intermediate.

Although the amino acid derivative shown by the formula (IV) is obtainedin the form of sodium salt by the above reaction, the sodium ion iseasily removed by cation-exchange chromatography. Further, sincet-butoxycarbonyl group is unstable toward cation-exchangechromatography, it is preferable that an alkaline metal ion is removedby cation-exchange chromatography using a pyridinium ion instead ofproton as a counter ion in view of preventing decrease of yield.

Since this step is a simple one step reaction called hydrolysis and doesnot require column chromatography difficult for the application to amass production, the amino acid derivatives shown by the formula (IV)can be prepared in a high yield, and further the application to a massproduction is easy.

The process of the amino acid derivative of the invention does not usean alkaline condition. In the meantime, there are many functionalmolecules except bases constituting a nucleic acid, which are unstabletoward alkaline conditions. Therefore, the process of the invention ispreferably used in case of preparing amino acid derivatives in aimingtheir use as base substances for introducing functional molecules.

It is determined that the amino acid derivative shown by the formula(IV), which are the final product, becomes any amino acid derivative inaccordance with a type of R¹ and value of n in the ester shown by theformula (VI).

The yield of the above reaction is reduced by steric hindrance dependingon the type of R¹ Therefore, R¹ is preferably a hydrogen atom or astraight chain or branched chain alkyl group with 1-5 carbon atoms, morepreferably a hydrogen atom or a straight chain or branched chain alkylgroup with 1-4 carbon atoms, furthermore preferably a hydrogen atom, amethyl or ethyl group. Further, R² is preferably a straight chain orbranched chain alkyl group with 1-4 carbon atoms, more preferably amethyl, ethyl, n-propyl or isopropyl group, and furthermore preferablyan ethyl group.

Further, in order to synthesize the compound of the general formula(IV), which is different in n, the correspondingbenzyloxycarbonyl-ω-amino acid can be used. Generally, since thebenzyloxycarbonyl-ω-amino acids of n=1−11 are commercially available, itis easy to obtain them. Names thereof are as follows.

Upper column: general name n Lower column: rational formula n = 1N-Benzyloxycarbonylglycine Z-NH—CH₂—COOH n = 2N-Benzyloxycarbonyl-β-alanine Z-NH—(CH₂)₂—COOH n = 3N-Benzyloxycarbonyl-4-aminobutanoic Acid Z-NH—(CH₂)₃—COOH n = 4N-Benzyloxycarbonyl-5-aminopentanoic Acid Z-NH—(CH₂)₄—COOH n = 5N-Benzyloxycarbonyl-6-aminocaproic Acid Z-NH—(CH₂)₅—COOH n = 6N-Benzyloxycarbonyl-7-aminoheptanoic Acid Z-NH—(CH₂)₆—COOH n = 7N-Benzyloxycarbonyl-8-aminooctanoic Acid Z-NH—(CH₂)₇—COOH n = 8N-Benzyloxycarbonyl-9-aminononanoic Acid Z-NH—(CH₂)₈—COOH n = 9N-Benzyloxycarbonyl-10-aminodecanoic Acid Z-NH—(CH₂)₉—COOH n = 10N-Benzyloxycarbonyl-11-aminoundecanoic Acid Z-NH—(CH₂)₁₀—COOH n = 11N-Benzyloxycarbonyl-12-aminododecanoic Acid Z-NH—(CH₂)₁₁—COOH

Among these, Z-glycine, n=1, can in particular preference, be used.

Since generally PNA is expected to be a hybrid with DNA, derivatizationsterically similar to DNA is desirable. In case the carboxylamino acidis used as a linker, Z-glycine is most preferable considering thispoint.

EXAMPLE

The invention will be illustrated in more detail by way of examples, butthe invention is not limited to these examples.

Example 1 Synthesis of Z-gly-^(BOC)PNA-OEt

To the dimethylformaamide solution (DMF; 25 ml) ofbenzyloxycarbonylglycine (Z-glycine; 6.75 g, 33 mmol) and ethyl N(2-aminoethyl)glycine (4.06 g, 17 mmol) was

added triethylamine (TEA; 4.78 ml, 35 mmol) and the mixture was stirredat 0° C. This was added with1-ethyl-(3-(3-dimethylaminopropyl)carbodiimide (EDCI; 6.79 g, 35 mmol)and stirred at 0° C. for 2 hours and further at room temperature for 15hours. The reaction liquid was added with ethyl acetate (EtOAc; 300 ml)and sequentially washed with aqueous 5% sodium bicarbonate solution(NaHCO₃; 300 ml×3), aqueous 5% citric acid solution (300 ml×3), aqueoussaturated sodium chloride solution (300 ml×3). The EtOAc layer was driedover anhydrous magnesium sulfate (MgSO₄) and then filtered whereby thefiltrate was concentrated. The residue was subjected, to silicagelcolumn chromatography (3% MeOH/dichloromethane) to obtain quantitativelyZ-gly-^(BOC)PNA-OEt as a colorless oil. ¹H NMR (CDCl₃) δ7.4-7.2 (m, 5H),5.77 (brt) and 5.68 (brt) (1H), 5.39 (brs) and 4.97 (brs) (1H), 5.27 (s)and 5.09 (s) (2H), 4.19 (m, 2H), 4.07 (s) and 3.91 (s) (2H), 4.01 (s,2H), 3.51 (brs) and 3.40 (brs) (2H), 3.34 (brs) and 3.25 (brs) (2H),1.40 (s, 9H), 1.26 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃) δ 169.71 and169.31 (3) 169.20 and 168.79 (d), 156.11 and 155.85 (d), 136.39 and136.32 (d), 128.44, 128.27, 127.98, 127.90, 79.80 and 79.37 (d), 66.86and 66.77 (d), 62.05 and 61.58 (d), 49.43 and 48.73 (d), 48.52 and 48.05(d), 42.49 and 42.34 (d), 38.48, 28.27, 14.03; FABMS m/z 438 [(M+H)⁺].

Example 2 Synthesis of Z-gly-^(BOC)PNA-OH

To the THF solution (20 ml) of Z-gly-^(BOC)PNA-OEt (4.0 g, 9.2 mmol) was

dropped aqueous 1N-NaOH solution (20 ml, 20 mmol) at 0° C., and thereaction liquid was stirred at 0° C. for 1 hour. After the reaction wascompleted, the reaction liquid was directly allowed to cation-exchangechromatography (DOWEX 50W×8, pyridinium form) and eluted with MeOH. Theeluate was concentrated under reduced pressure and further dried invacuum to obtain Z-gly-^(BOC)PNA-OH (3.09 g, 82%) as a colorless oil. ¹HNMR (DMSO-d6) δ 7.4-7.2 (m, 5H), 6.84 (brt) and 6.73 (brt) (1H), 5.03(s) (2H), 4.11 (brs) and 3.94 (brs) (2H), 3.92 (brs) and 3.77 (brs)(2H), 3.33 (brs) and 3.29 (brs) (2H), 3.09 (brs) and 3.02 (brs) (2H),1.37 (s, 9H); ¹³C NMR (DMSO-d6) δ 171.07 and 170.02 (d), 169.39 and169.07 (d), 156.42 (brd), 155.70 and 155.61 (d), 137.14, 128.35, 127.77,127.67, 78.04 and 77.76 (d) 65.38, 48.99, 47.43 and 46.70 (d), 41.92 and41.52 (d), 38.13 and 37.81 (d), 28.23; FABMS m/z 410 [(M+H)⁺]; HRMS(FAB⁺) calcd for C₁₉H₂₈O₇N₃ [(M+H)⁺]410, 1849, observed 410, 1926.

Example 3 Synthesis of Gly-^(BOC)PNA-OH

To the MeOH solution (20 ml) of Z-gly-^(BOC)PNA-OH (4.09 g, 10 mmol) was

added palladium carbon (5% Pd/C; 100 mg), and the catalytic hydrogenreduction was carried out at room temperature. After the reaction wascompleted, the mixture was filtered through celite. The residue wassubjected to silicagel column chromatography (5% MeOH/dichloromethane)to obtain Gly-^(BOC)PNA-OH (2.08 g, 75%) as white powder. ¹H NMR(DMSO-d6) δ 3.72 (brs) and 3.69 (brs) (2H), 3.58 (brs) and 3.54 (brs)(2H), 3.3-3.2 (m, 2H), 3.06 (brs) and 2.94 (brs) (2H); FABMS m/z 276[(M+H)⁺].

INDUSTRIAL APPLICABILITY

The process of the invention is able to realize industrial synthesizingwith high efficiency amino acid derivatives, which are utilized forphoto-functional PNA synthesis method.

1.-5. (canceled)
 6. A process comprising a step to obtain compoundsshown by the general formula (V):

by hydrolysis of the compounds shown by the general formula (VI):

wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms, and n means any one of integers 1-11and R² means a straight chain or branched chain alkyl group with 1-4Carbon atoms.
 7. The process according to claim 6, wherein thehydrolysis of the compounds shown by the general formula (VI) is carriedout by an aqueous alkaline mmetal hydroxide solution.
 8. The processaccording to claim 7, further comprising a step in which alkaline metalion is removed by cation-exchange chromatography using pyridinium ion asa counter ion.
 9. The process according to claim 7, wherein the alkalinemetal is selected from the group consisting of lithium, sodium andpotassium.
 10. The process according to claim 6, further comprising thestep of obtaining the compounds shown by the general formula (VI) by thereaction of benzyloxycarbonyl-ω-amino acids shown by the general formula(VII) below:

wherein n means any one of integers 1-11 and the compounds shown by thegeneral formula (II):

wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms, and R² means a straight chain orbranched chain alkyl group with 1-4 carbon atoms. 11-12. (canceled) 13.The process according to claim 10, wherein the compounds shown by thegeneral formula (II) are obtained by reaction of t-butoxycarbonylamineprepared from ethylenediamine and a compound shown by the generalformula (III)

wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms, R² means a straight chain or branchedchain alkyl group with 1-4 carbon atoms, and n means any one of integers1-11 .
 14. The process for the compounds shown by the general formula(V):

wherein R¹ means a hydrogen atom or a straight chain branched chainalkyl group with 1-5 carbon atoms, R² means a straight chain or branchedchain alkyl group with 1-4 carbon atoms, and n means an integer of 1-11)comprising the step of obtaining the compounds shown by the generalformula (V) by hydrolysis of the compounds shown by the general formula(VI):

wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms, R² means a straight chain or branchedchain alkyl group with 1-4 carbon atoms, and n means any one of integers1-11.
 15. The process for the compounds shown by the general formula(VI):

wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms, R² means a straight chain or branchedchain alkyl group with 1-4 carbon atoms, and n means an integer of 1-11,comprising the step of obtaining the compounds shown by the generalformula (VI) by reaction of benzyloxycarbontl-ω-amino acid shown by thegeneral formula (VII):

wherein n means any one of integers 1-11 and a compound of the generalformula (II):

wherein R¹ means a hydrogen atom or a straight chain or branched chainalkyl group with 1-5 carbon atoms, andR^(2 means a straight chain or branched chain alkyl group with) 1-4carbon atoms. 16-18. (canceled)